Published Online
on March 23, 2006

A more recent version of this article appeared on May 1, 2006

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Submitted on September 22, 2005
Revised on November 2, 2005
Accepted on December 6, 2005

Evidence for Involvement of Both IK_Ca and SK_Ca Channels in Hyperpolarizing Responses of the Rat Middle Cerebral Artery

Alister J. McNeish PhD; Shaun L. Sandow PhD; Craig B. Neylon PhD; Mark X. Chen PhD; Kim A. Dora PhD; and Christopher J. Garland PhD^*

From the Department of Pharmacy and Pharmacology (A.J.M., S.L.S., K.A.D., C.J.G.), University of Bath, Bath, UK; the Department of Physiology and Pharmacology (S.L.S.), University of New South Wales, Sydney, NSW, Australia; the Department of Anatomy and Cell Biology (C.B.N.), University of Melbourne, Parkville, Victoria, Australia; and Gene Expression and Protein Biochemistry (M.X.C.), GlaxoSmithKline R&D, Herts, UK.

^* To whom correspondence should be addressed. E-mail: c.j.garland{at}bath.ac.uk.

Background and Purpose--Endothelium-derived hyperpolarizing factor responses in the rat middle cerebral artery are blocked by inhibiting IK_Ca channels alone, contrasting with peripheral vessels where block of both IK_Ca and SK_Ca is required. As the contribution of IK_Ca and SK_Ca to endothelium-dependent hyperpolarization differs in peripheral arteries, depending on the level of arterial constriction, we investigated the possibility that SK_Ca might contribute to equivalent hyperpolarization in cerebral arteries under certain conditions.

Methods--Rat middle cerebral arteries (175 µm) were mounted in a wire myograph. The effect of K_Ca channel blockers on endothelium-dependent responses to the protease-activated receptor 2 agonist, SLIGRL (20 µmol/L), were then assessed as simultaneous changes in tension and membrane potential. These data were correlated with the distribution of arterial K_Ca channels revealed with immunohistochemistry.

Results--SLIGRL hyperpolarized and relaxed cerebral arteries undergoing variable levels of stretch-induced tone. The relaxation was unaffected by specific inhibitors of IK_Ca (TRAM-34, 1 µmol/L) or SK_Ca (apamin, 50 nmol/L) alone or in combination. In contrast, the associated smooth-muscle hyperpolarization was inhibited, but only with these blockers in combination. Blocking nitric oxide synthase (NOS) or guanylyl cyclase evoked smooth-muscle depolarization and constriction, with both hyperpolarization and relaxation to SLIGRL being abolished by TRAM-34 alone, whereas apamin had no effect. Immunolabeling showed SK_Ca and IK_Ca within the endothelium.

Conclusions--In the absence of NO, IK_Ca underpins endothelium-dependent hyperpolarization and relaxation in cerebral arteries. However, when NOS is active SK_Ca contributes to hyperpolarization, whatever the extent of background contraction. These changes may have relevance in vascular disease states where NO release is compromised and when the levels of SK_Ca expression may be altered.

Key words: EDHF • endothelium • nitric oxide • pharmacology • potassium channels

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